ABSTRACT The ch14.18 mAb recognizes GD2 on human melanomas (MEL) and neuroblastomas (NBL), and has recently been proven to prevent recurrences of high risk NBL when combined with GM-CSF and IL2. The hu14.18-IL2 immunocytokine (IC) links IL2 to the hu14.18 anti-GD2 mAb. This IC mediates much more potent antitumor activity in mice than the combination of Ab and IL2, particularly in the setting of non-bulky disease. Our phase I and II trials, in patients (pts) with MEL and NBL, show that hu14.18-IL2 is safe and induces immunologic activation. Complete tumor responses were observed, particularly in NBL pts with nonbulky disease. The goal of this project is to further evaluate and enhance the antitumor efficacy of hu14.18-IL2, through the following specific aims: 1. Evaluate the antitumor effects of hu14.18-IL2 in 3 clinical trials: i) A Phase II trial in children with NBL [through the Children's Oncology Group (COG)] to confirm the antitumor activity seen in NBL pts with nonbulky disease, and to pilot-test a combined regimen that the COG is committed to include in a separate upcoming Phase III trial. ii) A pilot study in stage 3 and 4 MEL pts who achieve no evidence of disease (NED) status with surgery, to test whether the activity achieved in NBL pts will be seen in MEL pts with high probability of relapse. This study will also evaluate, via immunohistochemistry, the in vivo response of the tumor to intravenous (IV) hu14.18-IL2 in pts with resectable metastatic MEL. Pilot data on the time to recurrence for pts achieving NED status with surgery and subsequent treatment with IC will also be collected. iii) A phase I/II clinical trial of hu14.18-IL2 injected directly into MEL lesions. This intratumoral (IT-IC) trial will evaluate toxicity and antitumor effects clinically and histologically. 2. Measure the in vivo effects of hu14.18-IL2: Blood and tumor specimens from treated pts will be tested for biologic and immunologic factors to help clarify the mechanisms of antitumor effects and of toxicity. 3. Increase antitumor efficacy of hu14.18-IL2 preclinically in tumor-bearing mice: We will test our hypothesis that enhanced antitumor efficacy will result from augmenting the level and longevity of IC binding to tumor cells and from combining hu14.18-IL2 with clinically applicable agents in order to simultaneously induce distinct mechanisms of tumor recognition and destruction.